A 65 year-old man with a Large Right Maxillary Mass.
July, 2020, Case 2007-1. Home Page

Kar-Ming Fung, M.D., Ph.D. Last update: June 11, 2020.

Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.

Clinical information: The patient was a 65 year-old man was referred to our institute because of a large mass in his right maxillary sinus with extension to the ethmoid sinus, and the orbit. A biopsy was performed. The patient was treated with radiaiton therapy and a hemi-maxillectomy with enucleation of the right globe was performed.

Radiology of the Case: There was large destructive mass (Panel A) that occupied the bulk of the space of the right maxillary sinus with destruction of the floor of the orbit and anterior wall of the maxillary sinus. Invasive fungal infection could generate this type of picture but the clinical story did not go along with it. A malignant tumor was the most likely diagnosis in this case. The epicenter of the tumor did not seem to be of osseous origin. This made osseous based tumors such as osteosarcoma and hematopoietic tumors such as lymphoma and plasmacytoma less likely. With this type of growth pattern and the location both taken into consideration, an epithelial neoplasm, most likely a carcinoma, was the leading differential diagnosis.  

Biopsy:

     
A.
CT		 B.
Cytologic Smear
 C.
Cytolotic smear		 D.
Frozen		 E.
Frozen		      
     
F. G.
 		H.
 		I. J.
S100		      

Pathology of the biopsy: An intra-operative consultation was performed. The cytologic preparation (Panel B, C) yielded atypical cells with large nuclei with some of them having a small amount of cytoplasm (Panel B). Frozen sections revealed a moderately cellular spindle cell tumor with some intervening collagen fibers (Panel D, E). There was no epithelial component. No prominent nucleoli were noted in either preparation. A frozen section diagnosis of spindle cell neoplasm was made.

The permanent section of the biopsy showed some variation in histopathologic picture. In some areas, there were spindle cell proliferation (Panel F, G) composed of cells with small nuclei and a moderate amount of cytoplasm. In a minor proportion of areas, there were some clearing of cytoplasm with vague epithelioid features. Some small nucleoli were present but there was no large, prominent nucleoli nor pseudonuclear inclusion.

The leading differential diagnoses based on histopathology was a sarcomatoid carcinoma versus a sarcoma.

Immunohistochemistry of the biopsy:

Comment on the biopsy: Both were not present in this case. The focal epithelioid changes can be suggestive of a sarcomatoid carcinoma, melanoma, or sarcoma with focal epithelioid change. The negative results for cytokeratins and the histopathologic features did not provide a strong suggestion of a sarcomatoid carcinoma although these tumor tend to lose epithelial markers often. The positive immunoreactivity for S100 and Sox10 in addition to the spindle cell neoplasm are suggestive of a malignant peripheral nerve sheath tumor (MPNST) and melanoma. This tumor is negative for MART-1, tyrosinase, and HMB45 which does not support a diagnosis of melanoma. The presence of a small number of MitF positive cells suggested melanoma. However, MitF can be positive in a small percentage (8%) of MPNST [Gaspard M et al., 2018]. S100 is often negative or totally lost in MPNST. The amount of S100 immunoreactivity was still moderately preserved. This finding was not in favor of MPNST. The immunohistochemical profile was, therefore, in favor of melanoma but MPNST could not be entirely ruled out.

Resection: 
K. L. M. N. O. P. Q.
Alcian blue
 
R. S. T.
Sox10		 U.
MitF		 V.
MitF		 W.
MitF		  

Pathology of the resected specimen: The resected specimen is rather heterogeneous in histopathologic changes. The minor part of the tumor was composed of high grade spindle to epithelioid cells with large nuclei and a moderate to large amount of cytoplasm. There was wide variation in nuclear sizes and pseudonuclear inclusions were common (Panel K, L). The major part of this tumor was composed of a chondroid neoplasm with a high (Panel M, N) to moderate cellularity (Panel O, P). The chondroid areas were positive on Alcian blue. The lacunae are well formed (Panel N, P). A small amount of residual mucosa were also present. In a small focus where preseved mucosa was present, high-grade dysplasia was noted (Panel R, S).

Immunohistochemistry of the resected specimen: The dysplastic cells were positive for Sox10 and MitF (Panel T, U). These cells suggested melanoma in situ. Sox 10 and MitF were variably positive (Panel V) and negative (Panel W) in the chondroid area. The spindle cell areas also showed similar variation but the spindle cells were more likely to be positive for both markers.

Molecular profile: No mutation was detected by pyrosequencing in BRAF V600E, K601E, or K601Q, IDH1 codon 132 or IDH2 codon 172.

Comment on pathology: With the melanoma in situ identified, the histopathologic features, and the immunohistochemical profile taken into consideration, this tumor is best interpreted as a chondroid malignant melanoma. The pseudonuclear inclusions, a feature of melanoma, is much more obvious in the resection. The increase in pleomorphism and nuclear in the resected specimen may be resulted from the radiation therapy. Last, but not the least, one must acknowledge that the chondroid component was not present in the biopsy material. Mutations in IDH1 and IDH2 are found in about 50% of the cases in chondrosarcoma. The lack of mutations in these two genes does not entirely rule out a diagnosis of chondrosarcoma but it does not support this diagnosis in this chondroid tumor.

DIAGNOSIS: Chondroid melanoma (chondrosarcomatous melanoma).

Discussion: General Information    Pathology   Immunohistochenistry   Molecular Pathology    Differential diagnosis   Related Cases

General Information:

Sinonasal cancer is uncommon with an overall incidence of 0.566 cases per 100,000 population per year with a male to female ration of 1.8:1. Almost 80% of these cases are seen in the nasal cavity (43.9%) and maxillary sinus (35.9%). Squamous cell carcinoma constitutes about half (51.6%) of all of the cases of sinonasal cancer. About 12.6% of sinonasal cancer are adenocarcinoma. Melanoma (6.6%), esthesioneuroblastoma (6.3%), and adenoid cystic carcinoma (6.2%) have comparable incidence. The rest are undifferentiated carcinoma (3.1%) and others (13.7%) [Turner JH and Reh DD, 2012].

Sinonasal melanoma occurs most commonly in the 7th and 8th decade [Clifton N et al., 2011; Gandy I et al., 2006; Dréno M et al., 2017]. The incidence has increased steadily in the past few decades [Turner JH and Reh DD, 2012]. Most of them are seen in the nasal cavity and maxillary sinus. Rare locations of primary sinonasal melanoma include the sphenoid sinus [Busaba NY, 2000; Lynch SC et al., 2005]. Clinical presentations fall into three major patterns- epistaxis, obstruction of airway, or effects of local compression and destruction leading to cranial nerve paresis, visual impairment, headache, and hypopituitarism. Sinonasal melanomas tend to be high on T1 signal partly due to the presence of paramagnetic melanin and sometimes because of coexistent hemorrhage. Melanotic tumors will be higher on T1 signal than amelanotic tumors [Raghavan P and Phillips CD, 2007]. The 5-year relative survival is poor with a relative survival of 34.7 months [Turner JH and Reh DD, 2012]. Pigmentation and pseudopapillary architectures are two features associated with worse outcome in sinonasal melanoma [Moreno MA et al., 2010].

Pathology:

In addition to the classic variant of melanoma, there are many unusual variants of melanoma [Benerjee SS & Eyden B, 2008; Magro C et al., 2006; Cota C et al., 2019; Saggini A et al., 2019]. These variants include angiomatoid melanoma, “animal-type” melanoma (pigmented synthesizing melanoma, balloon cell melanoma (sebocyte-like melanoma, pseudolipoblastic melanoma, melanoma with clear cells, and granular cell melanoma), basosquamous melanoma (basomelanocytic tumor and squamomelanocytic tumor), blue nevus-like melanoma and melanoma arising in blue nevi (“malignant blue nevus”), bullous/acantolytic melanoma, carcinoid-like melanoma, clear cell sarcoma, dermal melanoma, desmoplastic melanoma, follicular melanoma, ganglioneuroblastic melanoma, “invisible” melanoma (epithelioid melanoma in situ), lentiginous melanoma on the sundamaged skin of the elderly, lichenoid keratosis-like melanoma, melanoma resembling MPNST, melanoma with aberrant immunophenotype, micromelanoma, monster cell melanoma, multinucleated cell melanoma, myxoid melanoma, nested melanoma of the elderly, neurotrophic melanoma and melanoma with neural differentiation, nevoid melanoma, osteo-cartilagineous melanoma, pigmented epithelioid melanocytoma, plasmacytoid melanoma, plexiformmelanoma (deep penetrating nevus-like melanoma), polypoid melanoma, pseudoglandular melanoma, regressing melanoma (melanoma with complete regression), rhabdoid melanoma, sarcomatoid melanoma, signet ring cell melanoma, small cell melanoma, spindle cell melanoma, syringotrophic melanoma, verrucous melanoma and melanoma with pseudoepitheliomatous hyperplasia, and others.

Now we can see that melanoma can mimic a variety of entities that span from plasmacytoma (plasmacytoid melanoma) to adenocarcinoma (signet ring cell melanoma, pseudoglandular melanoma) to clear cell carcinoma (balloon cell melanoma) to verrucous carcinoma (verrucous melanoma and melanoma with pseudoepitheliomatous hyperplasia) to squamous cell carcinoma (basosquamous melanoma) to spindle cell tumor (desmoplastic sarcoma and sarcomatoid melanoma). In order not to fall into these diagnostic pitfalls, one must remember that many melanomas are amelanomatic. If the melanin pigment is present, it would be a big help but the chance is that they are not there. So, being familiar with these variants and a high index of suspicion is the best way to avoid these pitfalls.

Osteo-cartilagineous melanoma (also known as chondrosarcomatous and osteosarcomatous melanoma) [Ali AM et al., 2018] contains component with osseous or cartilagineous metaplasia in pure or mixed form [Benerjee SS & Eyden B, 2008; Lucas DR et al., 1993; Devesa PJ et al., 2013]. This variant is more common on acral skin [Sweeney SP & Royer MC, 2020; Emanuel PO et al., 2007], subuncal region [Devesa PJ et al., 2013; Pisano C et al., 2020; ], and in mucosal melanomas [Sweeney SP & Royer MC, 2020; Ackley CD et al., 2001; Ali AM et al., 2018; Benerjee SS & Eyden B, 2008; Hoorweg JJ et al., 1997]. Melanomas with only chondroma and devoided of osseous component are rare and only 21 cases have been reported [Sweeney SP & Royer MC, 2020]. Many of these cases are associated with a history of recurrent trauma or previous surgery suggesting that chronic reparative process may contribute to the production of chondroid component [Murali R et al., 2010; Piana S et al., 2009; Rinaggio J et al., 2008; Banerjee SS et al., 1998; Grunwald MH et al, 1985]. In some cases, osseous and chondroid metaplasia are noted in the metastasis [Piana S et al., 2009; Grunwald MH et al, 1985; McKay KM et al., 2012; Hoorweg JJ et al., 1997]. This suggest that the change in microenvironment may be responsible for triggering the metaplastic changes.

In general, the osteo-cartilagineous component usually makes up only a small part of the tumor [Saggini A et al., 2019]. The current case defied this general rule. Recognition of in situ melanoma, areas with pagetoid spread, or areas with classic features of melanoma would provide important diagnostic clue. With these features considered, misdiagnosis do not happen often [McKay KM et al., 2012; Emanuel PO et al., 2007].

Immunohistochemistry:

Immunohistochemistry and molecular pathology can provide further characterization of these cases. Markers such as MART-1, tyroinase, HMB45, Sox10, and S100 can be used to reveal the melanocytic nature of these tumors. It is important to remember that melanoma specific markers can be negative at least focally in the osseous and chondroid component as illustrated in this case.

It is equally important to know that that the chondroid and osseous component can be positive for Sox9 and STAB2 which are two markers that have specificity for chondroid and osseous differentiation [Ali AM et al., 2018; McKay KM et al., 2012]. These marker can be used to recognize the chondroid and osseous differentiation but it cannot be used to identify the underlying melanoma.

Molecular Pathology:

Very little data is available for melanoma with chondroid metaplasia. In one case, an NRAS Q61 mutation was detected [Sweeney SP & Royer MC, 2020].

Differential Diagnosis:

Diagnosis of osteo-cartilagineous melanoma can be challenging particularly with small biopsy. When a small biopsy contains exclusively of the osseous or chondroid component, the histopathologic features will suggest osteosarcoma and chondrosarcoma. In detail search of areas that are histologically classic for in situ or invasive melanoma is the first step and this case serves as a great example.

Sarcoma and sarcomatoid carcinoma in general: A high index of suspicion is very important. One must remember that epithelial neoplasm is far more common than melanoma which, in turn, is more common than sarcoma in a mucosa lined anatomic structure such as the areodigestive tract. Besides, osteo-cartilagineous metaplasia may also occur in carcinoma [Wargotz ES & Norris HJ, 1997; Ikoma S et al., 2017; Marioni G et al., 2004; Yokoo H et al., 1999]. The first step, therefore, is to rule out sarcomatoid and metaplastic carcinoma or melanoma. In contrast, genuine extraskeletal chondrosarcoma and osteosarcoma other than mesenchymal chondrosarcoma extremely uncommon to present as a mucosal or soft tissue based mass. Also, the extent of osseous and chondroid metaplasia only represent a small volume of the tumor in most cases. So, a detail examination of the non-osseous, non-chondroid area would provide good help. Immunohistocheistry for epithelial markers and melanoma can be used to reveal the nature of these tumors.

Apocrine chondroid syringoma (apocrine mixed tumor): This is an uncommon cutaneous tumor that occurs in the head and neck region of middle-aged and elderly patients. Extremities are uncommon sites. Histologically, it has a myxoid, chondroid, and fibrous stroma populated by an epithelial component with cells arranged I clusdes, cords, and ductal structure. Other than the chondroid matrix, it has very little resemblance with chondroid melanoma.

Mesenchymal chondrosarcoma: This tumor is characterized by cartilaginous islands surrounded by highly cellular sarcomatous component. It has a high incidence to occur as an extraskeletal tumor and often occurs in the head and neck region. These tumor are negative for MART-1 and HMB45. IRF2BP2-CDX1 fusion was demonstrated in 10 of 15 cases of mesenchymal chondrosarcomas [Nyquist KB et al., 2012] which can be used as a diagnostic aid.

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